Abstract
As the SARS-CoV-2 (COVID-19) pandemic spreads and the number of Bruton's tyrosine kinase inhibitor (BTKi)-treated COVID-19-affected patients grows, we must consider the pros and cons of BTKi discontinuation for our patients. In favor of BTKi continuation, BTK plays an active role in macrophage polarization. By modulating key transcription factors, BTK may regulate macrophage polarization downstream of classic M1 and M2 polarizing stimuli and mitigate the hyperinflammatory state associated with COVID-19. In favor of BTKi discontinuation, we note a potentially increased risk of secondary infections and impaired humoral immunity. We hypothesize that the potential benefit of blunting a hyperinflammatory response to SARS-CoV-2 through attenuation of M1 polarization outweighs the potential risk of impaired humoral immunity, not to mention the risk of rapid progression of B-cell malignancy following BTKi interruption. On the basis of this, we suggest continuing BTKi in patients with COVID-19.
In the setting of the evolving COVID-19 pandemic, providers must consider how to optimally manage patients with hematologic malignancy. There is rationale both for and against continuation of BTK inhibitors in patients on these drugs for management of CLL and B-cell lymphomas. Herein, we describe both benefits and risks of BTK inhibitor continuation.
Thousands of patients with chronic lymphocytic leukemia (CLL) and B-cell lymphomas are currently treated with Bruton's tyrosine kinase inhibitors (BTKi), including ibrutinib, acalabrutinib, and zanubrutinib. As the SARS-CoV-2 (COVID-19) pandemic spreads and the number of BTKi-treated COVID-19-affected patients grows, we must consider the pros and cons of BTKi discontinuation for these patients. A recent survey of CLL specialists conducted by the CLL Society showed stark disagreement regarding BTKi management. 40% reported that they were in favor of BTKi continuation and 60% reported that they would discontinue BTKi for COVID-19 patients or would only continue in certain clinical scenarios (1). To fully inform this decision, one must consider the potential protective anti-inflammatory effects of BTKis versus the theoretical risk of humoral immunosuppression.
SARS viruses are known to induce a hyperinflammatory state, in part, through M1 macrophage–associated activity, which not only promotes viral spreading via increased lymphocyte and infected monocyte flux, but also causes massive cell death, depletion of monocytes and macrophage “burn out” leading to the clinical consequences of COVID-19 (2). Later stages of COVID-19 are similarly marked by systemic hyperinflammation with potentially life-threating cardiopulmonary collapse and massive cell death (3). Thus, blunting SARS-CoV-2 induced cytokine storm may be important in mitigating pulmonary, cardiac, and vascular system injury. In COVID-19, laboratory markers of systemic inflammation (i.e., IFNγ, IL2, IL6, MIP1-α) are elevated, again providing evidence that activation of T cells and monocytes, with polarization of macrophages to an M1 state is fundamental in this immune dysregulation (4, 5). Targeted immunomodulatory drugs that decrease the M1 macrophage inflammatory response may minimize organ damage by blocking activation of the TH1/M1 inflammatory cascade.
BTK plays an active role in macrophage polarization by regulating transcription factors, such as NF-κB and IFN-regulatory factors (6–10). By modulating these transcription factors, BTK may regulate macrophage polarization downstream of classic M1- and M2-polarizing stimuli (11). For example, in Btk knockout mice, impaired recruitment of M1 macrophages and preferential polarization toward an M2 phenotype support BTK as a key in regulator of M1 polarization. Moreover, BTK-deficient macrophages are not only defective in inducing proinflammatory cytokines, but preferentially polarize toward anti-inflammatory M2 macrophages, even in response to proinflammatory stimuli (11). Additional preclinical studies have examined the effect of ibrutinib in the setting of influenza A infection. For mice lethally infected with influenza A virus, ibrutinib improved overall survival with resolution of infection, attenuation of lung inflammation, and reduced levels of inflammatory cytokines (12).
Although these data support the potential utility of BTKi in the setting of COVID-19, one also must consider the potentially increased risk of secondary infections or impaired humoral immunity in patients on BTKis. Opportunistic infections, particularly pneumonia, are commonly reported with ibrutinib and other BTKi, with a systematic review showing that 56% of ibrutinib-treated patients experienced an infectious complication (13). With 3 years of follow-up, 6% of patients receiving first-line ibrutinib and 25% of relapsed/refractory patients receiving ibrutinib developed pneumonia (14). Ibrutinib has been shown to affect humoral immunity; IgG levels remain stable during the first 12 months of ibrutinib therapy but subsequently fall over time, while IgA levels increase over time (15, 16). During ibrutinib exposure, normal B cells levels increase but continue to remain abnormally low (15). These findings are consistent with the clinical observation that the frequency of infections appears to decrease over time, especially after the first 6 months of ibrutinib (15, 16).
The effect of BTKi on the host's ability to develop immunity to SARS-CoV-2 or to a SARS-CoV-2 vaccine must also be considered. Patients with CLL are known to have decreased responses to vaccination; the seroconversion of untreated CLL patients to influenza vaccine is reported in the range of 10%–50% (17–19). Data on the effect of BTKi on vaccine efficacy is limited and mixed. A study of 19 ibrutinib-treated patients demonstrated that 26% (5/19 patients; 95% CI: 9.2%–51.2%) seroconverted to at least one strain of influenza following vaccination, a proportion within the range of reported seroconversions in untreated patients with CLL (20). Conversely, two smaller studies suggested that patients treated with BTKi may have inferior vaccine responses [0/13 ibrutinib-treated patients vaccinated for influenza seroconverted (21), 0/4 ibrutinib treated patients had immune response to PCV13 vs. 4/4 untreated CLL patients (22)]. Whether BTKi effects on the humoral immune system prevent the development of immunity to SARS-CoV-2 infection remains to be seen.
In patients who receive BTKi for therapy of B-cell malignancies, we hypothesize that the potential benefit of blunting the hyperinflammatory response to SARS-CoV-2 through attenuation of M1 polarization to mitigate the immediate risk of COVID-19-related mortality outweighs the potential medium- to long-term risk of impaired humoral immunity. The risk of rapid progression of B-cell malignancy following interruption further supports the argument for continuation of BTKi. On the basis of this, we suggest continuing BTKi in patients with COVID-19, though practitioners should maintain a low threshold to discontinue in the setting of significant clinical decompensation. Furthermore, toxicity of BTKi, which may vary by agent within the class, should be considered in light of clinical context and COVID-19-mediated organ dysfunction. Clinical trials are now underway to test BTKi as potential therapy for COVID-19 in patients without B-cell malignancies.
Disclosure of Potential Conflicts of Interest
E.A. Chong is an employee/paid consultant for Novartis, Tessa, and BMS. L.E. Roeker holds ownership interest (including patents) in AbbVie and Abbott Laboratories and is an advisory board member/unpaid consultant for AbbVie and Verastem Oncology. M. Shadman is an employee/paid consultant for Abbvie, Genentech, Astra Zeneca, Sound Biologics, Pharmacyclics, Verastem, ADC Therapeutics, Cellectar, Bristol Myers Squibb and Atara Biotherapeutics, and reports receiving commercial research grants from Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, Astra Zeneca, Sunesis, Acerta Pharma, Beigene and Merck. M.S. Davids is an employee/paid consultant for AbbVie, Adaptive Biosciences, Ascentage Pharma, AstraZeneca, Belgene, Celgene, Genentech, Gilead Sciences, Janssen, MEI Pharma, Phamacyclics, Research To Practice, Syros Pharmaceuticals, TG Therapeutics, Verastem, Zentalis, and reports receiving commercial research grants from AstraZeneca, Ascentage Pharma, Bristol-Myers Squibb, Genentech, MEI Pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, and Verastem. S.J. Schuster is an employee/paid consultant for Acerta, AlloGene, AstraZeneca, BeiGene, Celgene, DavaOncology, Gilead, LoxoOncology, Nordic Nanovector, Novartis Israel, Novartis AG, Novartis US, Novartis UK, Pfizer, Genentech/Roche, and Tessa Therapeutics, reports receiving commercial research grants from Novartis, TG Therapeutics, Genentech/Roche, AbbVie, Acerta, Incyte, Celgene/Juno, Merck, DTRM Bio., and Portola Pharm. A.R. Mato is an employee/paid consultant for TG Therapeutics, Celgene, Loxo, Pharmacyclics, Abbvie, Genentech, J and J, Sunesis, Verastem, Adaptive, reports receiving commercial research grants from Celgene, Pharmacyclics, and Abbvie, and is an advisory board member/unpaid consultant for CLL Society and NCCN. No potential conflicts of interest were disclosed by the other authors.
Authors' Contributions
Conception and design: E.A. Chong, L.E. Roeker, M. Shadman, S.J. Schuster, A.R. Mato
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.R. Mato
Writing, review, and/or revision of the manuscript: E.A. Chong, L.E. Roeker, M. Shadman, M.S. Davids, S.J. Schuster, A.R. Mato
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): A.R. Mato
Acknowledgments
This research was funded, in part, through the NIH/NCI Cancer Center Support Grant P30 CA008748 (to A.R. Mato, L.E. Roeker).
